Breast cancer remains the most commonly diagnosed cancer and second leading cause of cancer deaths in American women, despite significant advances in early detection and treatment. The genetic and molecular heterogeneity of breast cancer represents a challenge for treatment and prevention strategies, and the development of innovative targeted therapies for specific tumor subtypes is essential. Overexpression of HER-2/neu, a receptor tyrosine kinase, defines a molecular subtype of breast cancer associated with poor clinical outcome. Our data in the HER-2/neu transgenic mouse model show marked suppression of mammary tumorigenesis by dietary n-3 polyunsaturated fatty acids (PUFAs) compared to n-6 PUFAs, suggesting that HER-2/neu-mediated carcinogenesis might be uniquely susceptible to dietary fat content. We are proposing this developmental project to investigate the mechanisms by which dietary fat content modulates HER-2/neu-positive breast cancer. We hypothesize that dietary n-3 PUFAs inhibit HER-2/neuinduced mammary carcinogenesis by preventing HER-2/neu activation and function through disruption of critical interactions at the plasma membrane. To this end, we developed three specific aims for in vitro and in vivo studies to: 1) determine the effects of n-3 and n-6 PUFAs on protein-membrane interactions critical to HER-2/neu signaling during HER-2/neu-induced mammary carcinogenesis; 2) identify the effects of n-3 and n-6 PUFA supplementation on HER-2/neu-mediated signal transduction in breast cancer; and 3) define the effects of dietary fat content on the expression of FAS and COX-2 in breast cancer, as potential surrogate biomarkers of HER-2/neu activity. This proposal will provide the scientific basis for more extended studies of this novel gene-nutrient interaction in breast cancer, with identification of biomarkers of early events in HER- 2/neu signaling susceptible to n-3 PUFA suppression that can be used in clinical trials of dietary fat nterventions for breast cancer prevention and treatment. [unreadable] [unreadable]